Prostaglandins play a major role in the inflammation process and the inhibition of prostaglandin production, especially production of PGG.sub.2, PGH.sub.2 and PGE.sub.2, has been a common target of antiinflammatory drug discovery. However, common non-steroidal antiinflammatory drugs (NSAIDs) that are active in reducing the prostaglandin-induced pain and swelling associated with the inflammation process are also active in affecting other prostaglandin-regulated processes not associated with the inflammation process. Thus, use of high doses of most common NSAIDs can produce severe side effects, including life threatening ulcers, that limit their therapeutic potential. An alternative to NSAIDs is the use of corticosteroids, which have even more drastic side effects, especially when long term therapy is involved.
Previous NSAIDs have been found to prevent the production of prostaglandins by inhibiting enzymes in the human arachidonic acid/prostaglandin pathway, including the enzyme cyclooxygenase (COX). The recent discovery of an inducible enzyme associated with inflammation (named "cyclooxygenase-2 (COX-2)" or "prostaglandin G/H synthase II") provides a viable target of inhibition which more effectively reduces inflammation and produces fewer and less drastic side effects.
The references below that disclose antiinflammatory activity, show continuing efforts to find a safe and effective antiinflammatory agent. The novel oxazoles disclosed herein are such safe and also effective antiinflammatory agents furthering such efforts. The invention compounds are found to show usefulness in vivo as antiinflammatory agents with minimal side effects. The substituted oxazoles disclosed herein preferably selectively inhibit cyclooxygenase-2 over cyclooxygenase-1.
2,3-Diaryl-5-halo thiophenes are described in U.S. Pat. No. 4,590,205 as analgesic or antiinflammatory agents. More particularly, 2,3-diaryl-5-bromo thiophenes are described in U.S. Pat. No. 4,820,827 as having antiinflammatory and prostaglandin synthetase inhibitory activity for use in the treatment of inflammation and dysmenorrhea. PCT publication WO94/15932 describes 4,5-substitutedphenyl-thiophenes/furans and pyrroles as having antiinflammatory activity.
Pyrazole derivatives having antiinflammatory activity are described in U.S. Pat. No. 5,134,142, to Matsuo et al.
U.S. Pat. No. 3,578,671, to K. Brown, describes antiinflammatory 4,5-diphenyloxazoles substituted in the 2-position by a saturated or unsaturated aliphatic acid. U.S. Pat. No. 4,051,250, to J. Dahm et al, describes oxazole, imidazole and thiazole compounds, including 2-mercapto-4-(4-methylmercaptophenyl)-5-(4-chlorophenyl)oxazole, as having antiphlogistic, analgesic and antipyretic activity. Other related diphenyloxazole disclosures include U.S. Pat. No. 4,001,228, to G. Mattalia, for antiaggregating activity and U.S. Pat. No. 3,895,024, to R. Hafeli, for intermediates in the production of antiinflammatory agents. U.S. Pat. No. 4,489,084, to F. Haviv and F. Kerdesky, describes diphenyloxazolyl hydrazinoalkyl nitrile compounds for use as antiinflammatory agents. U.S. Pat. No. 4,143,047, to R. Harrison, describes oxazole compounds as reactants to make 2-acylamino oxazole derivatives having anti-allergy activity.
U.S. Pat. No. 4,791,124, to Lutomski et al, describes the pesticide activity of substituted bis(4-halophenyl)oxazoles. U.S. Pat. No. 4,775,687, to Meguro et al describes the possible use of 4,5-phenyl oxazoles as starting materials for antidiabetic compounds. WO publication No. WO92/21665, published Dec. 9, 1992, describes bis(halophenyl)oxazole derivatives as starting materials for the preparation of antiinflamnatory agents.
N. Meanwell et al [J.Med.Chem., 35, 3498 (1992)] describe bis(substitutedphenyl)oxazoles as having ADP-induced platelet aggregation inhibition activity.
U.S. Pat. No. 4,812,470, to N. Rogers et al, describes phenyl substituted oxazoles as having antibacterial activity.
U.S. Pat. No. 3,901,908, to K. Fitzi and R. Pfister, describes 2-alkyl and 2-cycloalkyl-4,5-phenyloxazoles as intermediates in the synthesis of imidazoles having analgesic and antipyretic activity. Specifically, 2-tert-butyl-4-(4-methylsulfonylphenyl)-5-phenyloxazole is described.
U.S. Pat. No. 4,632,930, to Carini et al, describes antihypertensive alkyl and aryl substituted imidazole, thiazole and oxazole derivatives. Specifically, 5-phenyl-4-(4-methylsulfonylphenyl)-.alpha.,.alpha.-bis(trifluoromethyl)th iazole-2-methanol is described.
R. Cremylin et al describe the synthesis of heterocyclic sulfonyl derivatives and specifically, 4',4"-(2-methyl-4,5-oxazoldiyl)-bis-benzenesulfonamide (J. Heterocycl.Chem., 22, 1211 (1985)).
T. van Es and O. G. Backeberg [J.Chem.Soc., 1363 (1963)] describe the synthesis of 2-methyl-4,5-substitutedphenyloxazoles, and specifically, 4-[5-(4-chlorophenyl)-2-methyl-4-oxazolyl]benzenesulfonamide.